Human Genome Project may help find treatment for muscular dystrophy

One of this country's most eminent geneticists is using results coming from the human genome project to help combat
muscular and nervous system disorders. She hopes that the knowledge gained will enable drugs to be developed that will
compensate for defects and effectively treat these devastating diseases.

Professor Kay Davies is head of the Department of Human Anatomy and Human Genetics at the University of Oxford. One of
the disorders her group is studying is Duchenne muscular dystrophy (DMD), one of 20 different types of muscular
dystrophy. DMD, which affects boys only, is caused by a lack of a protein called dystrophin, which joins the inside of
muscle fibers to the outside. The result of the defect is that the body's skeletal muscles gradually waste away and
affected individuals eventually lose their ability to walk.

The dystrophin gene is located on the X chromosome, which is present in duplicate in women and as a single copy in men.
This means that boys who inherit the disease will do so from a mother who carries one copy of the defective gene.
"Because it is one of the largest of all known genes, using gene therapy to introduce it into all affected muscle
cells, including those in the heart, is likely to be problematic," says Davies.

Even if this were feasible, there is also the possibility that patients would mount an immune response and reject the
protein. Her team therefore needed to find innovative ways of compensating for its absence.

In 1989, they made a key discovery by identifying a relative of dystrophin, called utrophin, whose gene was much
smaller than that of its big sister, but had similar functions.

The locations of utrophin and dystrophin are similar early in embryonic development - both are present at the junctions
between muscles and nerves and on the membranes of muscles. Later in development, utrophin is located only to the
nerve-muscle junctions. Davies and her team thought that if utrophin could be persuaded to relocate to the muscle
membrane then it may substitute for the missing dystrophin in DMD patients. "There are several examples of how the
absence of one gene can be compensated for by the presence of another," said Davies, "this is the rational behind the
replacing the missing dystrophin gene with utrophin in DMD."

Her group are presently identifying genetic sequences in the utrophin gene that may control the location of the
protein. "Every day we look at the freely available sequence information coming from the human genome project, says
Davies, "we are now piecing together these sequences to reproduce the entire regulatory region of the utrophin gene."
Armed with this knowledge, her team are pursuing two possible treatment options.

The first involves gene therapy. Here, the group plans to introduce the gene into viruses that will infect the muscle
cell and carry the utrophin gene with it, so the virus will produce utrophin protein that will travel to the muscle
membrane and the junctions between nerve and muscle. The problem here is to find a safe virus that will deliver the
gene to all muscle cells.

The other approach the team is actively pursuing aims to identify drugs that increase utrophin's production. If a
muscle cell produces extra utrophin, some will very likely be forced to move to the muscle membrane. They screen for
small chemical compounds by linking the regulatory region of the utrophin gene to another gene whose product can be
detected easily in cells, for example by fluorescence. They then screen thousands of chemicals in cells and look for an
increase in fluorescence.

Davies and her team have already started the screening test, and as more sequence becomes available, they will learn
more about the regulatory regions and be able to narrow down their search for drugs. "This screen may take two years to
complete, and the drug would then need to be processed through the usual clinical trials for efficacy and safety," says
Davies.

One of the most powerful uses of the HGP is that it can help to rapidly identify new genes that are related to known
ones. "We found the utrophin gene by chance," said Davies, "but if we deliberately set out to look for a relative of
dystrophin it may have taken 5 years or more before the advent of the HGP. It now could take a single day if the
sequences are already there."

Tracking down equivalent genes in other organisms - known as orthologues - is greatly aided by the human genome
project, says Davies. The HGP is being used to identify orthologues of important genes in the nematode worm
Ceanorhbditis elegans and the fruit fly Drosophila melanogaster, for example. "If organism has a known defect when a
specific gene is mutated, it can help define the gene's function in humans," she added.

Her group is using similar principles to identify genes involved in a related disorder called spinal muscular atrophy
(SMA). This disease, of which there are several types, is caused by mutations in a gene known as SMN, which causes loss
of motor neurons in the spinal cord. This motor neuron loss prevents some nerve impulses from being passed to muscles
and leads to weakness and wasting in affected individuals.

Davies' team have now identified other proteins that interact with SMN and have obtained partial gene sequences
corresponding to these proteins. They are presently scanning the data from the HGP in order to piece together the
full-length sequences of these genes, including the regions that control their activity.

She hopes that this short cut will save the group the years of effort needed to identify the genes and determine how
they are regulated. Once the sequence of the SMA-interacting genes is available, Davies plans to look for mutations in
patients with spontaneously arising SMA and in other neuromuscular disorders.

Colleagues at the Hammersmith Hospital in London are working with patients with these disorders and will collaborate
with Professor Davies on the project.

"The identification of genes that interact with SMN will be useful for two reasons," said Davies. "First, they may turn
out to be involved in other neuromuscular disorders. In addition, they may help to build of a picture of the complete
pathway in which SMN is just a player."

Anita Macaulay, Director of the Jennifer Trust for Spinal Muscular Atrophy said: "Professor Davies and her team are
conducting such vital work in understanding the genetics around SMA. We sincerely hope that this work will soon lead to
the answers that our families who live with SMA on a daily basis await."

"My daughter died from SMA Type I fifteen years ago - whilst any potential treatments are too late for her, I have
seven nieces and nephews who may be carriers and also at risk of having a child with SMA one day. I live in hope that
answers are found not only for my own family but for the many, many families who have experienced the pain of watching
a beloved baby die."

Notes to Editors:

Photographs of Professor Davies are available from the Press Office.

DMD affects 1 in 3,000 males, and around 1,500 boys with the disorder are living in the UK at any one time.
Muscular Dystrophy Campaign:
7-11 Prescott Place,
London SW4 6BS.
Tel: 020 7 720 8055
Web: www.muscular-dystrophy.org

SMA affects around 1 in 10,000 (boys and girls are both affected).
There are several different types of SMA with varying severity; see the website below for more details.
A family affected by SMA have expressed their willingness to talk to the media. Please contact the Wellcome Trust
Press Office for information. There are also some personal stories from families affected by SMA on the website
below.
Jennifer Trust for Spinal Muscular Atrophy:
Elta House,
Birmingham Road,
Stratford-upon-Avon,,br> Warwickshire,
CV37 0AQ.
Tel: (+44) 01789 267520;
Web: www.jtsma.demon.co.uk

Professor Davies is Head of the Department of Human Anatomy and Genetics at Oxford University. She is also
Honorary Director of the Medical Research Council Functional Genetics Unit in Oxford.
Professor Davies' work on DMD is funded by the MRC and the Muscular Dystrophy Group. Her work on SMA is funded by the
Jennifer Trust for Spinal Muscular Atrophy.

As part of the Joint Infrastructure Fund, the Wellcome Trust have recently funded a new Oxford Center for Gene
Functions. This is a collaboration between the Department of Physiology, headed by Professor F. M. Ashcroft, and Kay
Davies' Department of Human Anatomy and Genetics. The Wellcome Trust also funds Professor Davies in a number of other
areas of neurological and cardiovascular research.